Cervical Cancer
Cervical Cancer is a cancer of the female human cervix. It is the fourth-most common type of cancer and the fourth-most common cause of death from cancer in women. [1] Despite it being one of the most preventable and treatable cancers, it records an alarmingly high mortality rate (out of the 570,000 cases in 2018, 311,000 patients died (WHO)). About 90% of deaths occur in developing countries, with India accounting for 15.2% of Cervical Cancer deaths worldwide. [2] It causes extreme discomfort with symptoms including pelvic pain, painful vaginal bleeding, and discharge. The cancer drastically changes the patient’s life. It is a slow growing but life-threatening disease, that in critical stages could metastasize into other parts of the body like the lungs, liver, bladder, etc.
More than 95% of Cervical Cancer cases are caused by the Human Papillomavirus or HPV, a mostly sexually transmitted virus. Viral oncoproteins like E6 and E7 derived bind to, and induce the degradation of p53, a cellular tumour-suppressor protein. HPV causes other cancers too like anal, vulvar, penile, oral, etc.
HPV is mostly sexually transmitted and infects about 6.2 million new people each year, and basically, around 80% of the sexually active population. However, not all HPV infection leads to cancer. HPV infection is usually transient and asymptomatic, and it is usually taken care of by the host’s immunity in two to six months. Only when the infection is persistent does it evolve into something cancerous. There are almost 250 existing strains of HPV, heterogenous in carcinogenicity and ethnic dispersion. Most of the genotypes are not cancerous. HPV 16 and HPV 18 are the two most oncogenic types, causing approximately 70% of all cervical cancers, worldwide.
HPV infection often takes decades to develop into a tumour. Patients remain asymptomatic for long mainly because no immune system responses are triggered in initial stages of infection. If detected at an early stage, pre-cancerous cellular changes (dysplasia) due to HPV infection, and mild lesions can be treated before it becomes an invasive cancer. Thus, regular screening systems can ensure very effective control of cervical cancer.
In India, 483.5 million women are at the risk of developing cervical cancer. With 1 in 50 Indian women developing cervical cancer in their lifetime, it is the 2nd most common cancer among women in India, accounting for 15.2 percent of total cancer deaths in the world. Although studies show that deaths due to cervical cancer have been steadily declining in urban areas, the situation barely changes in rural areas.
Disproportionate Impact
The lack of a nationwide screening programme for HPV, dedicated health camps or any other such regulated systems to ensure rural populations get equal access to healthcare resources is one of the biggest reasons populations with lesser exposure and awareness are affected more severely by the effects of Cervical Cancer. Low- and middle-income countries are left vulnerable because of geography, traditional practices and beliefs, the screening levels, socioeconomic status, healthcare access, and public awareness. Sexual health and education continue to be taboo in mainstream discourse, especially among women in rural parts of India, which significantly impacts the odds of them actively seeking out tests and treatment, despite the prevalence of the disease. This is coupled with psychological factors like the fears of a painful and invasive test, anxieties about the results and embarrassment.
Another factor to consider is how available tests are simply not suited to being used easily in rural screening camps and low-resource settings- from sample collection being too invasive, to tests requiring sophisticated lab equipment that can only be handled by a trained professional.
Screening
Numerous studies have confirmed that effective control of the spread of Cervical Cancer is currently most lacking in its secondary stage of prevention, i.e., an accessible, and effective screening and testing programme facilitating early detection and treatment of HPV. Available tests when it comes to Cervical Cancer are the PAP-Smear, Hybrid Capture HPV DNA(HC2), Polymerase Chain Reaction (PCR), Visual Inspection with acetic acid and Lugol’s Iodine (VIA-VILI).
Visual Inspection – This method has generally been recognised by several studies as an attractive alternative to cytology-based screening, particularly in low-resource settings. It involves a visual examination of the uterine cervix after application of 3-5% acetic acid, and then Lugol’s Iodine, which colours pre-cancerous lesions differently. Benefits of VIA include its low cost and immediate results, at the cost of poor sensitivity due to the significant variability in the diagnosis of cervical dysplastic lesions and the need for trained professionals to inspect. The Indian Council of Medical Research’s (ICMR) Institute for Cytology and Preventive Oncology (ICPO) in collaboration with the US National Cancer Institute—Center for Global Health, held a 2-day brainstorming workshop in 2013 to and they were of the view that in most developing countries, due to the lack of necessary manpower, infrastructure and quality control, high-quality cytology screening may not be feasible for wide-scale implementation of the cervical cancer screening program. It was recommended that visual screening tests such as VIA/VILI could be adopted till a low-cost reliable HPV test became available in India.
Pap-Smear – The biggest reason for the lack of popularity of the pap-smear is the invasive sample collecting method. A special equipment called a speculum is required to dilate the vagina as sample is connected using a brush from cervical epithelial cells. The test also causes a lot of discomfort and general apprehension. Particularly for patients with pre-existing vaginal infections or swelling, this method is not recommended as it may aggravate the condition. It has poor reproducibility, and it can be affected by blood and mucus obscuration, imperfect fixation, and non-uniform distribution of cells. These issues amplify the difficulty in interpretation of results, and so, highly trained personnel are required. The sensitivity of the test is also not optimal as occasionally, atypical squamous cells of undetermined significance will lead to uncertain results. Such results require close, and constant follow up, which may lead to unnecessary referrals for colposcopy and treatment.
In the past, cytology-based methods such as the Papanicolaou (Pap) test were the highest standard to identify the disease at a stage where it can be treated. However, both the discussed methods have limitations when it comes to sensitivity. So, since the link between HPV and cervical cancer was identified, new tests began emerging directed towards identifying the virus, instead:
PCR- The HPV-PCR protocols use consensus primers such as PGMY09/PGMY1 and GP5+/GP6+, which allow amplification of many HPV genotypes in a single reaction. The primers target conserved regions of the HPV genome, such as the L1 capsid gene. The method is extremely sensitive, and this sensitivity is valuable in the areas where women will probably only be screened once or twice in their lifetimes. PCR techniques have some drawbacks, like in competition for reagents, leading to false negative results for multiple types of infections. Because of this problem, the PCR method may not detect all the HPV genotypes that are present in the sample. Amplification of samples containing DNA from more than one HPV genotype can lead to a much stronger amplification of one of the sequences present. This would complicate the detection of all genotypes in a sample with multiple infections.
Hybrid Capture- Matched to PCR in sensitivity, this FDA approved testing method lacks in being able to distinguish between different strains of HPV. As with PCR, the major drawback is the lack of specificity. Specificity is particularly important in cervical cancer screening because screening involves large numbers of otherwise healthy women, and positive results require a follow-up colposcopy that is both uncomfortable and costly. Instead of spending resources on huge numbers of patients with transient infections, our testing methods need to be specific to persistent, and oncogenic infections only. Specificity takes on added importance in low-resource settings where colposcopy is not available, and all women who test positive would then be expected to do further tests.
From these we see the need for a new method of screening that accessible, optimised to low-resource settings, and the comfort of the most vulnerable populations. We also find our solution in HPV DNA testing, and not dysplastic lesion detection, to ensure the test is non-invasive, sensitive, and not only identifies women with cervical disease but also those who are at risk for developing cervical neoplasia within the next 3 to 10 years. This is particularly important for developing countries that might not have sufficient resources to screen all women at 5- to 10-year intervals.
Along with sensitivity, we will address the shortcomings of PCR, etc. as our solution also ensures specificity to oncogenic, high-risk strains of HPV.
Vaccination
Another reason for our inability to tackle HPV infection are the extremely high prices of globally licensed vaccines that have been available in India so far. Lack of awareness among people along with HPV not being included in the Universal Immunisation Programme of India has resulted in people not realising the importance of the vaccination and being willing or able to afford the costs of the vaccine. In July 2021 however, CERVAVAC, a quadrivalent vaccination for HPV developed by Serum Institute of India (in collaboration with DBT, BIRAC and Bill Gates & Melinda foundation) was approved by the Drug Controller General of India and will probably be commercially available soon. It works based on VLPs (virus like particles) that generate antibodies specific to L1. The estimated price will be between 200-300 rupees, which is a tenth of current vaccine prices. Now, the next step is educating people about HPV, Cervical Cancer, and the importance of Preventive Healthcare
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References
1. Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, Bray F. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2020 Feb;8(2):e191-e203. doi: 10.1016/S2214-109X(19)30482-6. Epub 2019 Dec 4. Erratum in: Lancet Glob Health. 2022 Jan;10(1):e41. PMID: 31812369; PMCID: PMC7025157.
2. Srivastava AN, Misra JS, Srivastava S, Das BC, Gupta S. Cervical cancer screening in rural India: Status & current concepts. Indian J Med Res. 2018 Dec;148(6):687-696. doi: 10.4103/ijmr.IJMR_5_17. PMID: 30778002; PMCID: PMC6396551.
